Glucose is an important source of energy for most living organisms. The movement of glucose across membranes is accomplished by two classes of transporters, the energy dependent Na+-glucose cotransporters (Hediger, et al. (1989) Proc. Nat. Acad. Sci. USA 86, 5748-5752) and the facilitative glucose transporters. In humans, the facilitative glucose transporter family consists of at least six glucose transporters (Mueckler, et al. (1985) Science 229, 941-945; Fukumoto, et al. (1988) Proc. Nat. Acad Sci. USA 85, 5434-5438; Kayano, et al. (1988) J. Biol. Chem. 263, 15245-15248; Fukumoto, et al. (1989) J. Biol. Chem 264, 7776-7779; Ibberson, et al. (2000) J. Biol. Chem. 275, 4607-4612; Doege, et al. (2000) J. Biol. Chem. 275, 16275-80; Carayannopoulos, et al. (2000) Proc. Natl. Acad. Sci. USA 97, 7313-7318; Phay, et al. (2000) Genomics 66, 217-220) and a fructose transporter (Burant, et al. (1992) J. Biol. Chem 267, 14253-142; Davidson, et al. (1992) Am. J. Physiol. 262, C795-C800). These facilitative transporters regulate the movement of glucose between extra and intracellular spaces to maintain a constant supply of circulating glucose (Olson and Pessin. (1996) Annu. Rev. Nutr. 16, 235-256).
Defects in facilitative glucose transporters have been implicated in several metabolic disorders, including GLUT1 deficiency syndrome (Seidner, et al. (1998) Nat. Genet. 18, 188-91), Fanconi-Bickel Syndrome (Santer, et al. (1997) Nat. Genet. 17, 324-6) and Type 2 diabetes (Butler, et al. (1990) Diabetes 39, 1373-1380; Rothman et al. (1995) Proc. Nat. Acad. Sci. USA 92, 983-987; Cline, et al. (1999) N. Engl. J. Med. 341, 240-246). Type 2 diabetes is one of the most prevalent metabolic diseases, characterized by peripheral insulin resistance, impaired insulin production, and increased hepatic glucose production all contributing to hyperglycemia. Despite intensive investigation, the etiology of the disease remains unknown. The first glucose transporters identified (GLUT1-5) were extensively analyzed for mutations contributing to Type 2 diabetes, but to date no common causative mutation has been identified. However, several novel glucose transporters, GLUT8 and GLUT9 (Doege, et al. (2000) J. Biol. Chem. 275, 16275-80; Carayannopoulos, et al. (2000) Proc. Natl. Acad. Sci. USA 97, 7313-7318; Phay, et al. (2000) Genomics 66, 217-220), have recently been identified and additional glucose transporters may exist.
The results of several recent genetic linkage studies suggest that Type 2 diabetes in Caucasian patients is linked to the q12-q13.1 region of human chromosome 20 (Bowden, et al. (1997) Diabetes 46, 882-886; Ghosh, et al. (1999) Proc. Natl. Acad. Sci. USA 96, 2198-2203; Ji, et al. (1997) Diabetes 46, 876-881; Zouali, et al. (1997) Hum. Mol. Genet. 6, 1401-1408). Evidence of linkage disequilibrium with Type 2 diabetes has also been observed with alleles of two genetic markers within this linked region, adenosine deaminase (ADA) and D20S888, markers separated by approximately 6 cM (Price, et al. (1997) Am. J. Hum. Genet. 58 (suppl), A241).
The key metabolic role of glucose transport suggests that the identification of novel transporters may lead to new insights into the underlying biological processes of both glucose metabolism and Type 2 diabetes.